Obesity is associated with a decreased life span and many medical conditions including metabolic problems of insulin resistance, and diabetes mellitus and its many sequelae, including renal disease, eye disease, and cardiovascular disease. See Rissanen et al., 1990, Br Med J, 301:835-837.
Obesity is a risk factor for many conditions, particularly diabetes, more particularly Type II diabetes. Omental and mesenteric adipose depots, representing so-called visceral adiposity, are the fat depots most strongly associated with obesity-induced insulin resistance, especially in skeletal muscle and liver, so that a high level of visceral adipose tissue is associated with reduced glucose tolerance (Despres J P, 1993, Nutrition 9:452-459; Kissebah A H et al., 1994, Physiol Rev 74:761-811). For example, in men and in women the accumulation of intra-abdominal or visceral fat correlates with insulin resistance, whereas the deposition of subcutaneous fat only correlates with circulating leptin levels, rather than with insulin resistance (M Cnop et al., 2002, Diabetes, 51:1005-1015). Most significantly, the relationship between visceral fat deposition and glucose tolerance remains significant after correcting for the level of total-body fat. In other words, it is not only the amount of body fat that is important, the distribution or location of the body fat in the body is also important with the amount visceral fat being of greatest importance.
IGF-I admininstration in human subjects has had little effect on body fat and body composition. See Guevara-Aguirre et al., 1997, J Clin Endocrinol Metab 82:629-633, Mauras et al., 2000, J Clin Endcrinol Metab 85:3036-3042 and Laron et al., 1994, Clin Endocrinol 41:631-638 (Laron's Syndrome); Amhold et al., 2000, J Endocrinol Invest 23:258-262 (short stature in children lacking Growth Hormone gene); Grinspoon et al., 2003, J Clin Endocrinol Metab 88: 1142-1149 (anorexia nervosa); and U.S. Pat. No. 5,597,797. In these studies the effect of IGF-I on body fat distribution or visceral fat was not assessed.
In Japanese men, reduced IGF-I levels were associated with increased visceral fat and the fall in visceral fat associated with exercise was positively correlated with an exercise-induced increase in IGF-I levels. See Kunitomi M et al., 2002, Int J Obes Relat Metab Disord 26:361-369. However, the effect of administration of IGF-I on body fat in mammals has produced conflicting results. Recombinant human IGF-I injected in castrated male sheep lowered insulin levels, but had no detectable effect on body fat. See Certain et al., 1992, Endocrinol 130:2924-2930. This is consistent with their earlier work in mice. See Siddiqui et al., 1990, J Endocrinol, 124:151-158. In another study, IGF-I administered to rats, in which a catabolic state was induced by diabetes, dexamethasone, or intestinal resection, resulted in a trend toward a lower percentage of body fat. See Ballard et al. in Modern Concepts of Insulin-like Growth Factors, ed. Spencer, p. 617-627 (1991). In mini-poodles treated with recombinant human IGF-I, there was a reduced body mass index. See Guler et al., 1990, Acta Endo 121:456-464. Notably, in all of these studies, the effect on body fat distribution or visceral fat was not examined.
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. See Jung and Chong, 1991, Clinical Endocrinology, 35:11-20; Bray, 1992, Am J Clin Nutr 55:538S-544S. Protein-sparing modified fasting has been reported to be effective in weight reduction in adolescents. See Lee et al., 1992, Clin Pediatr, 31:234-236. Caloric restriction as a treatment for obesity causes catabolism of body protein stores and produces negative nitrogen balance. Protein-supplemented diets, therefore, have gained popularity as a means of lessening nitrogen loss during caloric restriction. Because such diets produce only modest nitrogen sparing, a more effective way to preserve lean body mass and protein stores is needed. In addition, treatment of obesity would be improved if such a regimen also resulted in accelerated loss of body fat. Various approaches to such treatment include those discussed by Weintraub and Bray, 1989, Med Clinics N Amer 73:237; Bray, 1991, Nutr Rev, 49:33.
Thus, there remains a need in the art for methods to reduce visceral fat, as well as to prevent visceral fat deposition, ameliorate visceral fat deposition caused by a medicament, and to provide for reduction of visceral fat as a part of weight loss induction.
The present invention address these needs